Acute exposure to 3‑deoxyglucosone at high glucose levels impairs insulin secretion from β‑cells by downregulating the sweet taste receptor signaling pathway

Abstract

Sweet taste receptors (STrs) expressed on β-cells stimulate insulin secretion in response to an increase in the circulating level of glucose, maintaining glucose homeostasis. 3‑D eoxyglucosone (3DG), a highly reactive α‑dicarbonyl compound, has been previously described as an independent factor associate with the development of prediabetes. In our previous study, pathological plasma levels of 3DG were induced in normal rats with a single intravenous injection of 50 mg/kg 3DG, and an acute rise in circulating 3DG induced glucose intolerance by impairing the function of pancreatic β‑cells. The present study aimed to investigate whether the deleterious effects of pathological plasma levels of 3DG on β‑cell function and insulin secretion were associated with STRs. IN S‑1 cells, an in vitro model to study rat β‑cells, were treated with various concentrations of 3DG (1.85, 30.84 and 61.68 mM) or lactisole (5 mM). Pancreatic islets were collected from rats 2 h after a single intravenous injection of 50 mg/kg 3DG + 0.5 g/kg glucose. The insulin concentration was measured by ELI SA. The protein expression levels of components of the STR signaling pathways were determined by western blot analysis. Treatment with 3DG and 25.5 mM glucose for 1 h significantly reduced insulin secretion by IN S‑1 cells, which was consistent with the phenotype observed in IN S‑1 cells treated with the STR inhibitor lactisole. Accordingly, islets isolated from rats treated with 3DG exhibited a significant reduction in insulin secretion following treatment with 25.5 mM glucose. Furthermore, acute exposure of IN S‑1 cells to 3DG following treatment with 25.5 mM glucose for 1 h significantly reduced the protein expression level of the STR subunit taste 1 receptor member 3 and its downstream factors, transient receptor potential cation channel subfamily M member 5 and glucose transporter 2. Notably, islet tissues collected from rats treated with 3DG exhibited a similar downregulation of these factors. The present results suggested that acute exposure to pathologically relevant levels of 3DG in presence of high physiological levels of glucose decreased insulin secretion from β‑cells by, at least in part, downregulating the STR signaling pathway.